HEPARIN SODIUM

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6-sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structural formula of heparin sodium (representative subunits): Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Carpuject™ sterile cartridge unit contain a sterile solution of Heparin Sodium Injection, USP. Heparin Sodium Injection 5,000 USP units/1 mL, single-dose cartridge, preserved with benzyl alcohol Each mL contains 5,000 USP units of heparin sodium and benzyl alcohol 1% as a preservative, in Water for Injection. The pH is adjusted between 5.0 to 7.5 with hydrochloric acid or sodium hydroxide. Heparin Sodium Injection 5,000 USP units/0.5 mL, single-dose cartridge, preservative-free Each 0.5 mL of preservative-free Heparin Sodium Injection contains 5,000 USP units in Water for Injection. The pH is adjusted between 5.0 to 7.5 with hydrochloric acid or sodium hydroxide as required. Chemical Structure

Heparin Sodium Injection is indicated for: • Prophylaxis and treatment of venous thrombosis and pulmonary embolism; • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease; • Atrial fibrillation with embolization; • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation); • Prevention of clotting in arterial and cardiac surgery; • Prophylaxis and treatment of peripheral arterial embolism; • Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures. Heparin Sodium Injection is an anticoagulant indicated for ( 1 ): • Prophylaxis and treatment of venous thrombosis and pulmonary embolism • Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease • Atrial fibrillation with embolization • Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation) • Prevention of clotting in arterial and cardiac surgery • Prophylaxis and treatment of peripheral arterial embolism • Use as an anticoagulant in blood transfusions, extracorporeal circulation and dialysis procedures

Recommended Adult Dosages: • Therapeutic Anticoagulant Effect with Full-Dose Heparin* ( 2.3 ) * Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. Deep, Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously Use a different site for each injection. Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.1 Preparation for Administration Confirm the choice of the correct Heparin Sodium Injection vial or cartridge prior to administration of the drug to a patient [see Warnings and Precautions (5.1) ] . Heparin Sodium Injection products must not be confused with “catheter lock flush” products. To lessen this risk for a cartridge, a red cautionary statement has been added to the cartridge and box/bin. Read the cautionary statement and confirm that you have selected the correct medication and strength. When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate. Administer Heparin Sodium Injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer Heparin Sodium Injection by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions (6) ] . 2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of Heparin Sodium Injection according to the patient’s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with Heparin Sodium Injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection. Periodic platelet counts, and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration. 2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect METHOD OF ADMINISTRATION FREQUENCY RECOMMENDED DOSE [based on 150 lb (68 kg) patient] Deep, Subcutaneous (Intrafat) Injection Initial dose 5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously A different site should be used for each injection to prevent the development of massive hematoma Every 8 hours or Every 12 hours 8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution Intermittent Intravenous Injection Initial dose 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP Intravenous Infusion Initial dose 5,000 units by intravenous injection Continuous 20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion 2.4 Pediatric Use Do not use benzyl alcohol-preserved drugs in neonates and infants. Use preservative-free Heparin Sodium Injection in neonates and infants [see Warnings and Precautions (5.4) ]. There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (Intravenous bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour) Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70 2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes. 2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous injection (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) with a fine (25- to 26-gauge) needle to minimize tissue trauma. 2.7 Blood Transfusion Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood. 2.8 Converting to Warfarin To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1) ] . 2.9 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered. 2.10 Extracorporeal Dialysis Follow equipment manufacturers’ operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturer’s recommendations are not available.

The use of Heparin Sodium Injection is contraindicated in patients with the following conditions: • History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions (5.3) ] • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.2) ] • In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin) • An uncontrolled active bleeding state [see Warnings and Precautions (5.2) ] , except when this is due to disseminated intravascular coagulation • Severe thrombocytopenia ( 4 ) • Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) ( 4 ) • When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals ( 4 ) • An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: • Hemorrhage [see Warnings and Precautions (5.2) ] • Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions (5.3) ] • Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4) ] • Thrombocytopenia [see Warnings and Precautions (5.5) ] • Heparin Resistance [see Warnings and Precautions (5.7) ] • Hypersensitivity [see Warnings and Precautions (5.8) ] • Hyperkalemia [see Warnings and Precautions (5.9) ] Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITT, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Heparin Sodium Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and precautions (5.2) ] . Gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: • Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin therapy, including fatal cases. • Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin therapy. • Retroperitoneal hemorrhage. • HIT and HITT, including delayed onset cases [see Warnings and Precautions (5.3) ]. • Local irritation - Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. Because these complications are much more common after intramuscular use, the intramuscular route is not recommended. • Histamine-like reactions - Such reactions have been observed at the site of injections. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin, occasionally requiring skin grafting [see Warnings and Precautions (5.3) ] . • Hypersensitivity - Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring less frequently. Itching and burning, especially on the plantar side of the feet, may occur [see Warnings and Precautions (5.8) ] . • Elevations of aminotransferases - Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. • Miscellaneous - Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. • Metabolism and nutrition disorders - Hyperkalemia.

Drugs that interfere with platelet aggregation: May induce bleeding. ( 7.2 ) 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained. 7.2 Platelet Inhibitors Drugs such as NSAIDS (including salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, and tirofiban), and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. To reduce the risk of bleeding, a reduction in the dose of antiplatelet agent or heparin is recommended. 7.3 Other Interactions Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Antithrombin III (human) – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human).

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Do not freeze. Discard unused portion after initial use.